Human Immunodeficiency Virus (HIV) is a serious public health threat. Other viral STDs including Herpes simplex virus (HSV) and Human Papilloma Virus (HPV) are also significant threats and the incidence of all three is rising rapidly. Infection with one viral STD can enhance acquisition of others. Since all three viruses cause persistent infection, once infected, the virus is not eliminated. Antivirals help but cannot clear the virus thus the most effective preventative strategy is to block infection. The applicant has identified a series of peptides that block infection with these viruses and the overall goal of this Program Project is to further development of these and other peptides for clinical use in preventing infection. The applicant will characterize the in vitro activity of the peptides, determine the mechanism of action, and measure in vitro toxicity. He will test structural variants to optimize the activity and when possible, test efficacy in appropriate animal models. The second goal of the Program is to use the existing and newly identified peptides as tools to study the process of viral infection. The Program Project consists of five components. Thee projects focus on specific viral STDs. A Peptide Design and Synthesis Core (Core A) directed by Dr. Brian Kay, will support the projects. An Administrative Core (Core B) directed by Dr. Brandt will oversee the Program. Project I, directed by Dr. Mirek Malkovsky, will focus on HIV. Project II, directed by Dr. Curtis Brandt, will focus on HSV, and Project III, directed by Dr. Paul Lambert will focus on HPV. The information gained by the proposed studies will be useful in moving the peptides toward clinical use as agents that can be included in a jelly applied by individuals to reduce or prevent sexual transmission of these viruses.